NF-κB Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages

Abstract

Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing β cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-κB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-κB and its role in regulating the APC function of macrophages (Mφ) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mφ prepared from NOD mice exhibited increased NF-κB activation relative to NOR and BALB/c Mφ. This hyperactivation was detected for different NF-κB complexes and correlated with increased IκBα degradation. Furthermore, increased NF-κB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mφ to secrete IL-12(p70), TNF-α, and IL-1α, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IκBα. In contrast, elevated NF-κB activation had no significant effect on the capacity of NOD Mφ to stimulate CD4+ or CD8+ T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mφ exhibit hyperactivation of NF-κB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-κB influences Mφ APC function by regulating cytokine secretion but not T cell stimulation.

Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice

“…26,27 Certain of the immune anomalies associated with NOD antigen-presenting cells (APC) also are more normal in NOR, including NF-kB regulation that promotes more normal control of IL-12p70, TNFa and IL-1a cytokine secretion. 28 Thus, a combination of NOR genes serve to suppress autoimmune diabetes development at both the T-cell and APC levels.…”

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

“…DC precursors in BM of NOD mice and BB-DP rats also show proliferation/differentiation abnormalities and from these precursors abnormal ''steady state'' DCs arise with a spontaneous high pro-inflammatory set point [29,30]. These abnormal DCs have a high level of NF-kB and a high acid phosphatase, high IL-12 and low IL-10 expression [31][32][33][34]. These DCs are incapable of sufficiently sustaining the proliferation of Treg-cell populations in the NOD mouse and BB-DP rat [35,36].…”

Defective up‐regulation of CD49d in final maturation of NOD mouse macrophages

“…This balance may be disturbed in NOD macrophages upon stimulation with LPS, leading to high levels of pERK-1/2 and consequent suppression of CD49d expression. Stimulation of NOD macrophages was previously reported to result in hyperactivation of NF-jB [5]. NF-jB might be involved in the regulation of CD49d expression.…”

“…The LPS-induced increase in NF-jB binding activity and the increase in the levels of IL-12p40 can be regulated independently of ERK-1/2 activation [19]. Furthermore, NF-jB hyperactivation in NOD macrophages was observed upon activation with various stimuli and was not exclusively restricted to activation with LPS [5]. Thus, NF-jB LPS is a well-studied exogenous activator of TLR-4.…”

“…NOD bone marrow-derived macrophages (BMDM) generated in vitro fail to mature functionally, and in vivo, such a defect may result in a reduced ability to efficiently activate regulatory T cells [4]. Furthermore, NOD BMDM exhibit hyperactivation of the transcription factor NF-jB, leading to elevated expression of IL-12(p70), promoting a Th1-driven immune response [5]. BMDM represent a homogeneous pool of primary macrophages derived from BM precursors.…”